4-(3-substituted amino)-2-hydroxypropoxy)-1,2,5-thiadiazoles

ABSTRACT

WHEREIN R is the 1,2,5-thiadiazole-4-yl group.   4-(3-(Substituted amino)-2-hydroxypropoxyl)-1,2,5-thiadiazole compounds, substituted by a nitrogen containing group in the 3position of the thiadiazole nucleus which exhibit Beta adrenergic blocking properties and thus are useful in the management of angina pectoris are described. The products are prepared by one of three principal methods (1) reaction of a 4hydroxy-1,2,5-thiadiazole with epihalohydrin to provide 4-(3halo-2-hydroxypropoxy)-1,2,5-thiadiazole which, upon treatment with alkali, forms the epoxide which is then reacted with an amine to provide the desired product; (2) reaction of a 3chloro(or bromo)-4-(3-substituted amino-2-hydroxypropoxy)-1,2,5thiadiazole with an amine or an N-containing heterocycle that replaces the 3-chloro group; and (3) reductive alkylation of an

United States Patent I [1 1 Wasson 1 1 Mar. 27, 1973 [541 4-(3-SUBSTITUTED AMINO)-2- HYDROXYPROPOXY)-1,2,5- THIADIAZOLES [75] Inventor: Burton Kendall Wasson, Valois,

Quebec, Canada [73] Assignee: Charles E. Frosst & Co., Kirkland,

Quebec, China /Taiwan [22] Filed: Sept. 9, 1971 [21] Appl. No.: 179,147

Related US. Application Data [60] Division of Ser. No. 818,090, April 21, 1969, Pat. No. 3,655,663, which is a continuation-in-part of Ser. No. 731,333, May 22, 1968, abandoned.

[52] US. Cl ..260/293.68, 260/268 H, 260/293.63, 260/306.8 D, 260/999 [51] Int. Cl. ..C07d 91/68 [58] Field of Search ..260/268 H, 293.63, 293.68, 260/3068 D [56] References Cited UNITED STATES PATENTS 3,488,360 1/1970 Weinstock et al ..260/302 Primary Examiner-Henry R. Jiles Assistant Examiner-G. Thomas Todd Attorney-Erma R. Coutts et al.

[57] ABSTRACT 4-[3-(Substituted amino)-2-hydroxypropoxyl]-1,2,5- thiadiazole compounds, substituted by a nitrogen containing group in the 3-position of the thiadiazole nucleus which exhibit B-adrenergic blocking properties and thus are useful in the management of angina pectoris are described. The products are prepared by one of three principal methods (1) reaction of a 4- hydroxy-l,2,S-thiadiazole with epihalohydrin to provide 4-(3-halo-2-hydroxypropoxy)-l,2,5-thiadiazole which, upon treatment with alkali, forms the epoxide which is then reacted with an amine to provide the desired product; (2) reaction of a 3-chloro(or bromo)-4-(3-substituted amino-2-hydroxypropoxy)- 1,2,5-thiadiazole with an amine or an N-containing heterocycle that replaces the 3-chloro group; and (3) reductive alkylation of an 0 RO-CH;-i 3-CHN1, R-0-CH (3-0N3,

O RooH i JCH=N0H, ROGH;-ii3-OH2NO:,

wherein R is the 1,2,5-thiadiazole-4-ylgroup.

8 Claims, No Drawings 4-(3-SUBSTITUTED AMlNO)-2- HYDROXYPROPOXY)-l ,2,5-THIADIAZOLES This application is a division of my copending US. Pat. application, Ser. No. 818,090, filed Apr. 21, 1969 (now US. Pat. No. 3,655,663), which in turn was a continuation-in-part of U.S. Ser. No. 731,333, filed May 22, 1968 (now abandoned).

This invention is concerned with 4-[3-(substituted amino )-2-hydroxypropoxy 1 ,2,5-thiadiazole compounds which are substituted in the 3-position of the thiadiazole nucleus by a nitrogen containing group. These compounds exhibit B-adrenergic blocking properties and have the marked advantages of having a long duration of action and being effective at very low dosage levels.

The novel B-adrenergic blocking agents of this invention have the structure and pharmacologically acceptable salts thereof, wherein R represents an amino having the structure NR"R wherein R represents hydrogen, lower alkyl having from one to four carbons and hydroxy substituted lower alkyl having from two to four carbons, R represents hydrogen, a lower alkyl having from one to four carbon atoms, hydroxy substituted lower alkyl and phenyl, or'R and R can be joined together directly to give a threeto 7-membered ring with the nitrogen to which they are attached thereby forming aziridinyl, azetidinyl, pyrrolidyl, piperidyl, or a hexahydroazepinyl group said 3- to 7-membered rings being either unsubstituted or substituted preferably with one or more lower alkyl having from 1 to carbons, hydroxy or hydroxy-lower alkyl of C substituents; R represents hydrogen and lower alkyl having a straight or branched chain containing from one to five carbons; R represents l) a straight or branched chain alkyl having from one up to about 20 carbons but preferably a branched chain alkyl having from three to 10 carbons such as isopropyl, tert-butyl, 2,2-dimethylpropyl and the like, (2) an unsaturated straight or branched chain alkyl as the alkenyl or alkinyl groups having preferably from two to six carbons, such as ally], butynyl, propargyl and the like, said straight or branched chained, saturated or unsaturated alkyl optionally being substituted with one or more groups preferably selected from (a) hydroxy, (b) di-lower alkyl (C amino wherein the alkyl groups optionally can be joined together directly to form a heterocyclic group selected especially from pyrrolidinyl, piperazinyl, piperidinyl, each group preferably being attached to an alkyl moiety having one to eight carbons, (c) phenyl or phenoxy optionally substituted with from one to three similar or dissimilar groups selected from alkoxy (C, alkyl (C halogen (preferably chloro) or hydroxy, (3) R also can represent a cycloalkyl group having from 3 to 6 nuclear carbons, optionally lower alkyl (C substituted such as the cyclopropyl, cyclopentyl, cyclohexyl, Z-methylcyclohexyl and the like; and when R and R separately represent lower alkyl or lower alkenyl they additionally can be joined together directly to form a 4- to 6-membered ring with the nitrogen to which they are attached which heterocycles can optionally be substituted with a lower alkyl (C to form, for example, the pyrrolidyl, piperidino, hexahydroazepinyl, A or A -piperidienyl, 1,2- dihydropyridyl and the like,

Suitable pharmacologically acceptable salts of product I are acid addition salts derived from inorganic acids, for example, hydrochlorides, hydrobromides, phosphates or sulfates or salts derived from organic acids, for example, oxalates, lactates, malates, maleates, formates, acetates, succinates, tartrates, salicylates, citrates, phenylacetates, benzoates, ptoluenesulfonates and other salts such as those that provide relatively insoluble products that afford a slow release of the active material, for example, a 1,140 methylene-bis(2-hydroxy-3-naphthoate) and the like.

The novel 4-[3-(substituted amino)-2-hydroxypropoxy]- l ,2,5-thiadiazole compounds, structure I, as well as their intermediates which contain one asymmetric carbon atom in the propylene chain will be obtained as racemic compounds which can be separated into optically active isomers by known methods, for example,

by forming a salt with an optically active acid, many of which are known to those skilled in the art, such as optically active tartaric, mandelic, cholic, 0,0-di-p-toluoyl tartaric, 0,0-dibenzoy1 tartaric acids, or other acids conventionally employed for this purpose. Those novel products and intermediate compounds that contain two or more asymmetric carbons in the propylene chain will be obtained as diastereoisomers, and each diastereoisomer, of course, also will be obtained as a racemic compound which can be separated into its optically active isomers by known methods such as described above. Resolution of certain representative intermediate and end products will be described in the detailed examples. All products can be similarly resolved and the claims will be understood to embrace the products in the form of racemic compounds or diastereoisomers as well as in the form of the optically active isomers where appropriate.

The potential of a product as a B-adrenergic blocking agent conventionally is evaluated by the protocol which was employed to assess the B-blocking properties of the thiadiazole compounds of this invention. The protocol employed comprises intravenous administration of graded doses of the selected compound to rats which are then challenged with a standard dose of isoproterenol, a product known to be a B-stimulant. The ED for representative products of this invention tested according to this protocol is included in certain of the examples that follow.

The clinical application of B-adrenergic blocking agents is well known to physicians. One use for the novel products of this invention, which constitutes the best mode for use of the products known to applicant at this time, is for the control of tachycardia that may be drug induced (as by isoproterenol) or brought about by 3 4 physiological conditions. In view of the considerable amines, particularly branched chain monoalkylamines, amount of literature that has accumulated concerning as neopentylamine, can be refluxed with the interthe use of B-adrenergic blocking agents, physicians mediate product C to give the desired product I would employ the products of this invention in any of directly. the known conditions where a short-acting or long-act- 5 Product I can be prepared by the reaction of starting ing agent is needed, such as in the management of ansubstance A with an oz-haloalkanoic acid of the strucgina pectoris. ture The products can be prepared in pharmaceutical formulations suitable for oral or parenteral administration hal CH2 CO2H preferably in the form of tablets, solutions, suspensions to ovide 3-R-4-a-carboxyalkoxy-l,2,5-thiadiazole n emulSlOnS The 1,2,54hiadia20le5 can be formuwhich is converted by conventional methods to the acid lated in the form of the free base or in the form of their hl id R i f th id hl rid with salts in conjunction or admixture with organic and/or diazomethane gives the 3- 4 3 z inorganic solid or liquid pharmaceutical excipients. No )-l,2,5-thi dia ole which upon reduction, preferably special problems are involved in preparing suitable forwith sodium borohydride, affords the intermediate C, mulations of these products and methods generally emhi h i converted t th thiadiazole l by the ployed for this purpose, which are known to those ro du de ibed above. skilled in this art, are entirely suitable. If desired the Many of the thiadiazole starting materials, A, are compounds can be administered along with or formuknown p ds or can be made from known startlated together with other active ingredients. Dosage i g materials. In general, the process for making the units of from about 2 mg. to 10 mg. can be provided for hi di l A comprises h reaction f an R the symptomatic adjustment of dosage by the physician (j1C]-[ CONH with monium hydroxide to provide depending upon the age and condition of the patient. h corresponding a-R-a-amino-acetamide The novel thiadiazole products I of this invention can hydrochloride which product, when reacted with SCI;,, be Prepared y one more of the following routes: S Cl SOCl or thionylaniline, provides the desired The 3-R-4-hydroxy-1,2,5-thiadiazole (A) is treated thiadiazole A. It is sometimes more convenient to with epichlorhydrin or epibromhydrin (B) to provide prepare the a-amino-acetamide product from an aproduct C which can be separated from the reaction amino acid such as an RCH(NH )CO H by treatmixture by extraction with ether. Ideally, the ment with acetyl chloride in methanol to form the ester epihalohydrin is used in excess for its solvent properties which upon treatment with a large excess of ammoniand the reaction proceeds at room temperature or with um hydroxide forms the desired a-amino-acetamide heating up to about 90 C. with optimum results being which then can be treated with SCI S Cl SOCI or obtained by heating at a temperature between about thionylaniline to provide the thiadiazole A.

-70 C. The reaction of A and B is additionally Another route by which novel compounds of this infacilitated by the presence of a trace of base which vention can be prepared can be illustrated asfollows: serves as a catalyst, preferred catalysts being piperidine, piperidine hydrochloride, pyridine or other ROUTE n heterocyclic bases. After extraction the intermediate 55 E product C is shaken with aqueous alkali to afiord the C1 H epoxide (D). Aqueous sodium or potassium hydroxide (Br) N N are preferred at a concentration of about 20 percent for best yields. Treatment of the epoxide D with the H1 amine E provides the desired thiadiazole product I. Advantageously an excess of the amine is employed for its solvent properties; from 3 to 5 moles of the amine being adequate to give very good yields of the desired N product. Larger quantities of course can be employed if S so desired. This step can be carried out at a temperature between about ambient temperature and C.

although it is preferred to use temperatures between In the second route, treatment of the thiadiazole, l-d,

about 6070 C. It has also been found that certain (prepared by the method described in Route 1) with an 5 6 amine, F, affords the appropriately 3-substituted Y is preferably a saturated or unsaturated lower alkyl product I-e. When the amine F is a primary or seconda- (C hydroxy-lower alkyl (C lower cycloalry amine, the reaction advantageously is carried out y a-6) of ph ny under pressure; however, when the amine is a heterocy- Z is lower alkyl l-5) and when cle of the type defined hereinabove the reaction readily 5 Y and Z are each lower alkyl y can be linked takes place without pressure by heating the reactants at together to form a to 6'membered eal'boeyehe a temperature between about l-l50 C. but ring with the carbon to which y a! e attached; preferably at a temperature between about l25l 35 R and Re have the meaning hereihbefol'e assigned- C. A slight excess of the amine F generally is used for AS catalyst, Palladium 0n Charcoal th um aluminum its Solvent properties and from about 3 to 5 moles of hydride asreducing agent, advantageously is employed. i h n f d to i optimum yields Larger The following examples will illustrate representative quantities can, of course be employed, if desired. Products of this invention Prepared y the above v i difi ti can be made in the above described procedures. It will be understood that these preferred methods for preparing the products of this incompounds can be P P y either Route I, H or III vention For example, when Starting material A in or a combination or modification of these routes as Route 1 is the 3 1 bromo) 4 hydroxy 1,2"5 described above. The following examples therefore are thiadiazole, it can be reacted with product F (see Route not to be considered as limiting the Preparation of y 11) h b i d i h d i d R group particular compound to the method described in the the 3-position of the thiadiazole nucleus. Also, when R example as the examples are Provided solely to thus in product D (see Route 1) is chloro or bromo, product trate the best modes currently known to applicant for v I) c n b reacted i h h amine F whereupon h the preparation of the novel thiadiazoles of this invenamine will first react with the epoxide portion of the product and then, by increasing the temperature, it will EXAMPLE 1 replace the chloro or bromo group thereby forming a product of the structure:

OH 3-Piperidino-4-(3-isopropylamino-2-hydroxypropoxy)- 1,2,5-thiadiazole Hydrochloride Step A: Preparation of 3-chloro-4-(2,3-epoxypropoxt y)-l,2,5-thiadiazole A mixture of 30 g. (0.22 moles) of 3-chloro-4- hydroxy-l,2,5-thiadiazole, 71 g. (0.77 moles) of Obviously an amine of the structure HNR R could be epichlorohydrin, and 0.6 ml. of piperidine is mainused in place of'reactant F. As is usual, the amine is emtained at 65-70 C. for 2 hours. Excess ployed in excess for its solvent properties and the epichlorohydrin is removed at about 95 C. using second state of the reaction advantageously is carried water-pump vacuum. The residual viscous gum, 55.5 out at a temperature from between about 1 l0-l 50 C. g., is dissolved in diethyl ether and refrigerated. The sualthough preferably at between about l25-l35 C. to pematant ethereal liquor is drawn off and evaporated introduce the amino group into the 3-position. In some 40 to dryness giving 20.2 g. of a viscous oil that is then instances it may be advantageous to carry outthis reacstirred for about one-half hour with 150 m1. of 10 pertion in a sealed vessel. cent sodium hydroxide solution. The mixture warms up A third route for preparing the novel products of this slightly during this treatment. The mixture then is exinvention comprises forming the substituted amino tracted with diethyl ether, washed with water, and group in situ by reductive alkylation illustrated by the evaporated to yield 20.2 g. of crude 3-chloro-4-(2,3-

. Step B: Preparation of 3-chloro-4-( 3-isopropylaminox is -0--0Hliic N,, O-CH ]-CN.1 2-hydroxypropoxy)-1,2,5-thiadiazole hydrochloride A mixture of 40.2 g. (0.2l mole) of 3-chloro-4-(2,3- epoxypropoxy)-l,2,5-thiadiazole and 76 g. (1.05 moles) of isopropylamine is heated and stirred at OH OH 6070 C. for 2 V2 hours. Excess isopropylamine is removed in vacuo giving 42.4 g. of residual crude product. The latter is dissolved by shaking with a mix- 0 ture of diethyl ether and water containing 2.5 g. of sodi- -o-oH -ii-ON urn hydroxide. The ethereal phase is separated and the aqueous phase is extracted with several portions of diethyl ether. The ethereal extracts are combined, washed with small volumes of water and then treated with excess 3N hydrochloric acid. The aqueous layer is separated, evaporated to dryness, and the resulting residue is dried by azeotropic distillation of benzene ethanol. The crystalline solid is recrystallized from ethanol diethyl ether giving 3-chloro-4-(3- isopropylamino-2-hydroxypropoxy )-l ,2,5-thiadiazo]e hydrochloride.

Step C: Preparation of 3-chloro-4-(3-isopropylamino- 2-hydroxypropoxy)- 1 ,2,5 -thiadiazole The 3chloro-4-( 3-isopropylamino-2-hydroxypropoxy)-l,2,5-thiadiazole hydrochloride obtained in Step B is neutralized with aqueous sodium carbonate and the free base extracted with diethyl ether. After removal of the solvent, the residue is recrystallized from diisopropyl ether giving the free base.

Step D: Preparation of 3-piperidino-4-( 3- isopropylamino-Z-hydroxypropoxy )-l ,2,5-thiadiazole hydrochloride A mixture of l 1.8 g. (39 millimoles) of 3-chloro-4-(3 -isopropylamino-2-hydroxypr0poxy)-1,2,5-thiadiazole hydrochloride from Step B, and 65.5 ml. (752 millimoles) of piperidine is heated and stirred at l25l 35 C. for 4 hours. This mixture is refrigerated overnight and the precipitated product is collected and dried. The excess piperidine is removed by distillation in vacuo, the residue is shaken with 10 ml. of water containing 1.6 g. of sodium hydroxide and extracted with diethyl ether. The combined ethereal extracts are washed sparingly with water and evaporated to dryness. The product is dissolved in anhydrous diethyl ether and treated with excess hydrogen chloride in diethyl ether to give a solid product which following recrystallization from anhydrous acetone-diethyl ether gives 3- piperidino-4-( 3-isopropylamino-2-hydroxypropoxy l,2,5-thiadiazole hydrochloride, m.p. 169170.5 C. (ED =O.13 mg/kg).

Analysis calculated for C H ClN O S:

C, 46.35; H, 7.48; Cl, 10.52; N, 16.63; S, 9.52;

Found: C, 46.71; H, 7.32; C], 10.58; N, 16.40; S,

Additional products of this invention that advantageously are prepared by the procedure described in Example 1 are identified in Table I, below. These products are synthesized by following the procedure identified in Example 1 but replacing the 3-chloro-4-(3 -isopropylamino-2-hydroxypropoxy)- l ,2,5-thiadiazole hydrochloride by the reactant I-d having the R substituent identified in the Table and replacing the piperidine employed in Example 1 by the amine reactant F having the substituents identified for this reactant in the following Table under the headings R and R". The R, R and R groups identified for the starting materials F and l-d are retained in the end product for which physical properties are provided.

Additional products of this invention that are prepared by the procedures described in Routes 1, 11 or [11 and more particularly illustrated by Example 1 are identified in the following Table. The compounds identified in Table I] wherein R is a group having the TABLE l Analysis Found Calculated Empirical formula 10. 2t! 16. Ol

10.1 Lin .Cli hC- cuUgsNiOgs-llcl Example number:

ti. T7

\ sMC cullmNiOts-cm o,

structure RR N are advantageously prepared from synthesized by the process substantially as described in the compound HI Example 1, Steps A and B, and then replacing the 3- (1 (III; (II nmNwm chloro by the R R N- group by reaction with the N selected amine by substantially the same procedure 5 described in Example 1, Step D.

ll ll CH C H 011 Preparation of the novel products of this invention from the 3-R-4-(3-amino-2-hydroxypropoxy)-1,2,5- thiadiazole is described in the following example.

EXAMPLE 4 3 -Piperidino-4-( 3-a-methylbenzylamino- 2- hydroxypropoxy)- l ,2,5-thiadiazole 3-Chloro-4-hydroxy-l,2,5-thiadiazole is treated with 2-chloroacetic acid in the presence of ethanolic sodium hydroxide to give 3-chloro-4-carboxymethoxy-1,2,5- thiadiazole. Treatment of this acid with thionyl chloride or oxalyl chloride affords the acid chloride, 3- chloro-4-chlorocarbonylmethoxy-l ,2,5-thiadiazole. This compound is treated with potassium cyanide by the usual method to give the cyanoketone, 3-chloro-4- cyanocarbonylmethoxy-l,2,5-thiadiazole which is hydrogenated in the presence of a catalyst such as palladium on charcoal or reduced withlithium aluminum hydride to give 3-chloro-4-(3-amino-2-hydroxypropox- .y)-l,2,5-thiadiazole. This amine, when reductively alkylated with acetophenone affords 3-chloro-4-(3-ozmethylbenzylamino-2-hydroxypropoxy)- l ,2,5- thiadiazole, which when reacted with piperidine by the process of Example 1, Step D, gives 3-piperidino-4-(3- a-methylbenzylamino-2-hydroxypropoxy)- l ,2,5- thiadiazole.

By replacing the cyanoketone and the acetophenone reactants employed in Example 4 by other 3-chloro-4- X-l,2,5-thiadiazoles and other O=CYZ ketones of the type identified for Route III, other 3-R-4- {3- [(CHYZ)NH ]-2-hydroxypropoxy} l ,2,5-thiadiazole compounds are obtained wherein the groupings R, X, Y and Z have the meaning assigned hereinabove in relation to Route III.

The invention further provides pharmaceutical compositions comprising, as active ingredient, at least one of the compounds according to the invention in association with a pharmaceutical carrier or excipient. The compounds may be presented in a form suitable for oral, rectal or parenteral administration. Thus, for

example, compositions for oral administration may be solid or liquid and may take the form of capsules, tablets, coated tablets, suspensions, etc., such compositions comprising carriers or excipients conveniently used in the pharmaceutical art. Thus suitable tabletting excipients include lactose, potato and maize starches, talc, gelatine, stearic acid, magnesium stearate, polyvinyl pyrrolidone, or other known tabletting substances.

For parenteral administration, the carrier or excipient may be a sterile, parenterally acceptable liquid, e.g., pyrogen-free water or an aqueous solution of polyvinyl pyrrolidone, or a parenterally acceptable oil, e.g., arachis oil, contained in ampoules.

In compositions for rectal administration, the carrier may comprise a suppository base, e.g., cocoa butter or a glyceride.

Advantageously, the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Tablets, coated tablets, capsules, ampoules and suppositories are examples of preferred dosage unit forms according to the invention. Each dosage unit adapted for oral administration may conveniently contain 1 to 20 mg., and preferably 2 to 10 mg., of the active ingredient; each dosage unit adapted for parenteral administration may conveniently contain 0.1 to 5 mg., and preferably 0.1 to 1 mg., of the active ingredient.

What is claimed is:

1. A 1,2,5-thiadiazole having the structure on RHI O-GHz-IL-CHFNRIU and pharmacologically acceptable salts thereof wherein R is a nitrogen-containing group of the structure NRR wherein R" is selected from hydrogen, lower alkyl and hydroxy substituted lower alkyl,

R is selected from hydrogen, lower alkyl and hydroxy substituted lower alkyl, or

R and R when lower alkyl can be linked directly together to form a 3- to 7-membered ring with the nitrogen to which they are attached or a substituted 3- to 7-membered ring wherein the substituent groups are selected from lower alkyl, hydroxy, or hydroxy-lower alkyl;

R is selected from the group consisting of hydrogen and lower alkyl;

R is selected from the group consisting of 1. C alkyl,

2. substituted C alkyl wherein the substituent groups are selected from (a) hydroxy, (b) dilower alkylamino, (c) pyrrolidinyl, (d) piperazinyl, (e) piperidinyl, (f) phenyl, (g) halophenyl, (h) lower alkoxyphenyl, (i) phenoxy, (j) lower alkoxyphenoxy, (k) lower alkylphenoxy, and

3. C cycloalkyl; and

R and R can be joined together to fonn with the nitrogen atom to which they are attached the pyrrolidyl, piperidino, hexahydroazepinyl.

2. A l,2,5-thiadiazole as claimed in claim 1 wherein R is piperidino of the structure wherein X is selected from the group consisting of hydrogen, hydroxy, lower alkyl and hydroxy-lower alkyl.

3. A 1,2,5-thiadiazole having the structure or a pharmacologically acceptable salt thereof wherein X is selected from the group consisting of hydrogen, hydroxy, lower alkyl and hydroxy-lower alkyl.

4. A 1,2,5-thiadiazole having the structure or a pharmacologically acceptable salt thereof.

8. A l,2,5-thiadiazole as claimed in claim 7 wherein the (C alkyl) is ten-butyl. 

2. substituted C1 10 alkyl wherein the substituent groups are selected from (a) hydroxy, (b) di-lower alkylamino, (c) pyrrolidinyl, (d) piperazinyl, (e) piperidinyl, (f) phenyl, (g) halophenyl, (h) lower alkoxyphenyl, (i) phenoxy, (j) lower alkoxyphenoxy, (k) lower alkylphenoxy, and
 2. A 1,2,5-thiadiazole as claimed in claim 1 wherein R is piperidino of the structure wherein X is selected from the group consisting of hydrogen, hydroxy, lower alkyl and hydroxy-lower alkyl.
 3. A 1,2,5-thiadiazole having the structure or a pharmacologically acceptable salt thereof wherein X is selected from the group consisting of hydrogen, hydroxy, lower alkyl and hydroxy-lower alkyl.
 3. C3 6 cycloalkyl; and R5 and R6 can be joined together to form with the nitrogen atom to which they are attached the pyrrolidyl, piperidino, hexahydroazepinyl.
 4. A 1,2,5-thiadiazole having the structure or a pharmacologically acceptable salt thereof.
 5. A 1,2,5-thiadiazole as claimed in claim 4 wherein the (C1 10 alkyl) is tert-butyl.
 6. A 1,2,5-thiadiazole as claimed in claim 4 wherein the (C1 10 alkyl) is isopropyl.
 7. A 1,2,5-thiadiazole having the structure or a pharmacologically acceptable salt thereof.
 8. A 1,2,5-thiadiazole as claimed in claIm 7 wherein the (C1 10 alkyl) is tert-butyl. 